Multiple Sclerosis (MS) is a chronic neuron-inflammatory demyelinating disorder of the Central Nervous System (CNS) that predominantly affects young adults in their 20s or 40s and is one of the most common causes of non-traumatic disability among young and middle-aged people. MS-related health care costs are estimated to be more than $10 billion annually in the United States, and $15 billion worldwide.
As of 2008, between 2 and 2.5 million people are affected globally with rates varying widely in different regions of the world and among different populations. MS affects more than 350,000 people in the United States and 2.5 million worldwide. In the United States, prevalence estimates are approximately 90 per 100,000 population.
MS symptoms can start anywhere between 10 and 80 years of age, but they usually begin between 20 and 40 years, with a mean age of 32 years. Women outnumber men by a ratio of 2-3 to 1, although in Primary Progressive MS (PPMS) the ratio is closer to equal,
The name multiple sclerosis refers to scars (sclera—better known as plaques or lesions) in particular in the white matter of the brain and spinal cord. The etiology of MS is unknown. It is believed to be an autoimmune disease, in which the body's immune system attacks its own tissues. In MS, this process destroys myelin, the fatty substance that coats and protects nerve fibres in the brain and spinal cord. When myelin is damaged, the messages that travel along that nerve may be slowed or blocked. MS is characterized by areas of de-myelinated plaques disseminated throughout the CNS with a predilection for optic nerves, spinal cord, peri-ventricular white matter (WM), corpus callosum, and cortical and sub-cortical grey matter (GM).
Later in the disease course, gradual progression of disability is observed. The overt progression of disability (secondary progressive MS) occurs when on-going irreversible tissue injury exceeds a critical threshold beyond which the nervous system can no longer compensate. At this point, the disease becomes essentially a degenerative process, with neurologic deterioration independent of on-going inflammation.
Multiple sclerosis is also known as “disseminated sclerosis” or “encephalomyelitis disseminate”. It is an inflammatory disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a wide range of signs and symptoms, including physical, mental, and sometimes psychiatric problems,
While the cause is not clear, the underlying mechanism is thought to be either destruction by the immune system or failure of the myelin-producing cells. Proposed causes for this include genetics and environmental factors such as infections. MS is usually diagnosed based on the presenting signs and symptoms and the results of supporting medical tests.
MS can be classified by the comparative severity of symptoms over time. Where new symptoms occur in isolated attacks, this is termed the “relapsing-remitting” form of MS. Relapsing Remitting (RRMS) is the most common form of the disease (85% of patients), wherein symptoms appear for several days to weeks, after which they usually resolve spontaneously.
Where new symptoms build up or become more severe over time, this is termed a “progressive” form of MS. Between attacks, symptoms may disappear completely; however, permanent neurological problems often occur, especially as the disease advances. Patients with progressive forms of MS have a markedly worse clinical outlook than do patients with a relapsing-remitting form. The present invention relates to pharmaceutical compositions for treating progressive forms of MS, and more particularly to treating Secondary Progressive (SP) and Primary Progressive (PP) forms of MS.
There is no known cure for multiple sclerosis. Treatments attempt to improve function after an attack and prevent new attacks. Medications used to treat MS while modestly effective can have adverse effects and be poorly tolerated. Many people pursue alternative treatments, despite a lack of evidence of efficacy. The long-term outcome is difficult to predict. Life expectancy is 5 to 10 years lower than that of an unaffected population. Above-average outcomes are more often seen in women, those who develop the disease early in life, and those who initially experienced few attacks. In the following paragraphs, an analysis is made of the 8 drugs that have been evaluated so far, in clinical trials for various prior art treatments for MS.
After tissue damage accumulates over many years, 50% of RRMS patients typically evolve to show Secondary Progressive MS (SPMS), in which pre-existing neurologic deficits gradually worsen over time and stop responding to standard MS therapies. So far, there are no inmunomodulatory treatment available to stop or reverse this form of MS.
Primary Progressive (PPMS) affects about 15% of MS patients; these patients have gradually worsening manifestations from the onset without clinical relapses, patients with PPMS tend to be older, have fewer abnormalities on brain MRI, and generally do not respond to standard MS therapies. About 15% of patients have PPMS from the onset. So far, there are no inmunomodulatory treatment available to stop or reverse this form of MS.
Progressive Relapsing (PRMS) entails gradual neurologic worsening from the onset with subsequent superimposed relapses. PPMS is suspected to represent SPMS, in which the initial relapses were unrecognized, forgotten, or clinically silent.
Interferon beta 1a, Interferon beta 1b and glatiramer acetate have failed to demonstrate efficacy in slowing down the disability progression. Therapies such as mitoxantrone, methotrexate, azatioprine and cyclophosphamide have poor methodological clinical studies where both RRMS patients are evaluated together with SP and PPMS patients, and do not show a reduction in the progression of disability. Finally, there is no evidence with natalizumab, fingolimod and teriflunomide; however, unpublished data would indicate no effect on the progressive forms. Therefore, current available drugs, including the disease modifying drugs used for RRMS, cannot reverse, halt or even slow down the progressive disability in the SP & PPMS forms.
Interferon beta-1a (IFNB-1a) has been tested for efficacy in Secondary progressive MS (SPMS). This testing included two clinical trials. The IMPACT study included a total of 436 subjects with Secondary progressive MS with relapses that were randomized to receive IFNB-1a weekly (intramuscular) or placebo for two years. The IMPACT data showed a significant benefit in the group of IFNB-1a in terms of MSFC decrease (40.4%, p=0.033), fewer relapses (33%, p=0.008), better outcome in eight of eleven MS Quality of Life scales and less MRI activity (p<0.001).
The SPECTRIMS study included a total of 618 patients with Secondary progressive MS with relapses who received IFNB-1a (three times weekly) or placebo for 3 years. The data showed that IFNB-1a did not significantly affect disability progression (p=0.146), although significant treatment benefit was observed on relapse rate (reduced from 0.71 to 0.50 per year, p<0.001) and on MRI outcomes.
Interferon beta-1b (IFNB-1b) has also been tested for efficacy in Secondary progressive MS in two clinical trials. In the EUSPMS: a total of 718 patients with Secondary progressive MS were randomized to IFNB-1b or placebo with treatment duration of up to three years. The EUSPMS data showed that the time to confirmed 1.0 point progression on the Expanded Disability Status Scale (EDSS) was delayed (p=0.007) and the progression of 2.0 EDSS point was 27% lower.
The NASPMS study included 939 subjects with Secondary progressive MS with relapses that were randomized to either placebo or IFNB-1b. The NASPMS data showed no treatment benefit on time to confirmed progression of disability, though relapse and MRI-related outcomes showed significant benefit. A combined analysis of both the EUSPMS and NASPMS trials shows that the patients with more pronounced disability progression and continuing relapse activity could be more likely to benefit from treatment.
For Primary progressive MS (PPMS), a Cochrane systematic review included two randomized controlled trials (entailing a total of 123 patients), and compared interferon treatment versus placebo in patients with PPSM. This review did not show differences regarding the proportion of patients with progression of the disease (RR 0.89, 95% CI 0.55 to 1.43), and it was associated with a greater frequency of treatment-related adverse events (RR 1.90, 95% CI 1.45-2.48). One of the trials showed a lower number of active MRI lesions at two years in interferon arm (difference −1.3, 95% CI −2.15 to −0.45, P=0.003).
Glatiramer Acetate was tested in a controlled clinical trial (Wolinsky 2007) wherein a total of 943 patients with PPMS were randomized. The data showed there was a non-significant delay in time to sustained accumulated disability (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p=0.1753).
In La Mantia 2010 (the Cochrane systematic review), data for 1049 patients with Primary progressive MS contributed to the meta-analysis. No benefit was shown in SPMS and PPMS patients. No major toxicity was found. The most common systemic adverse event was a transient and self-limiting patterned reaction of flushing, chest tightness, sweating, palpitations, and anxiety. Local injection-site reactions were observed in up to a half of patients treated with glatiramer acetate, thus making a blind assessment of outcomes questionable.
Mitoxantrone was evaluated in Hartung (2002), describing a controlled clinical trial of 194 patients with worsening RRMS or SPMS with relapses. Patients were assigned placebo or mitoxantrone; 188 patients completed the protocol and were able to be assessed at 24 months. At 24 months, the mitoxantrone group experienced benefits compared with the placebo group on different clinical measures (difference 0.3 [95% CI 0.17-0.44]; p<0.001), reducing progression of disability and clinical exacerbations.
Similarly, Martinelli (2005), the Cochrane systematic review, provides a meta-analysis of four clinical trials involving a total of 270 patients with RRMS, PRMS and SPMS with relapses. Meta-analysis showed that mitoxantrone reduced the progression of disability at 2 years follow-up (proportion of patients with 6-months confirmed progression of disability: Odds Ratios 0.3, p=0.05). These results, however, are based on heterogeneous trials in terms of drug dosage and inclusion criteria.
Cyclophosphamide was meta-evaluated in La Mantia (2007), a Cochrane systematic review. The meta-analysis included four RCTs comparing Cyclophosphamide to placebo or no treatment, entailing a total of 152 participants. The meta-analysis showed that cyclophosphamide did not prevent the long-term (12, 18, 24 months) clinical disability progression as defined as evolution to a next step of EDSS score. However, the mean change in disability (final disability subtracted from the baseline) significantly favoured the treated group at 12 (effect size −0.21, 95% confidence interval −0.25 to −0.17) and 18 months (−0,19, 95% confidence interval −0.24 to −0.14) but favoured the control group at 24 months (0.14, CI 0.07 to 0.21).
Methotrexate was studied in a trial with 60 progressive MS patients only. The results from Gray (2006) show there was a non-significant reduction in sustained EDSS progression and number of relapses in favour of methotrexate therapy. There were no data on relapse rate and no difference in time to first relapse. Minor side effects were reported in both methotrexate (87.1%) and placebo groups (89.7%), but there were no major side effects.
Rituximab was studied in 439 PPMS patients, randomized to intravenous rituximab or placebo. The data from Hawker (2009) showed differences in time to confirmed disease progression between rituximab and placebo did not reach significance (96-week rates: 38.5% placebo, 30.2% rituximab; p=0.14). From baseline to week 96, rituximab patients had less (p<0.001) increase in T2 lesion volume; brain volume change was similar (p=0.62) to placebo. Adverse events were comparable between groups.
The Azathioprine Cochrane systematic review (Casetta (2007)) included 698 randomized patients with all clinical forms of MS. The pooled data showed azathioprine reduced the number of patients who had relapses during the first year of treatment (relative risk reduction [RRR]=20%; 95% CI=5% to 33%), at two years (RRR=23%; 95% CI=12% to 33%) and three years (RRR=18%; 95% CI=7% to 27%) follow-up. These results were consistent in sensitivity analysis. There was no heterogeneity among the studies. Data from only three small trials with a total of 87 patients were available to calculate the number of patients who progressed during the first two to three years. There was a statistically significant benefit (RRR=42%; 95% CI=7% to 64%) of azathioprine therapy at three years' follow-up; this result was robust after sensitivity analyses.
The prior art thus teaches many potential therapies for MS. The art, however, also teaches that certain forms of MS remain resistant to any currently-known therapy.
Andrographolide (the claimed compound) and certain analogous compounds are taught by Juan Luis HANCKE et al., U.S. Pat. No. 8,080,495. That patent also teaches autoimmune diseases including “rheumatoid diseases, psoriasis, systemic dermatomycocytis, multiple sclerosis [and] lupus erythematosus.” See 1:29-39. Regarding multiple sclerosis, the patent says, “Using the mixture of andrographolides described in Example 9, normalization in the symptoms of the disease occurs following 3 months of treatment of the composition of the present invention. In addition, the composition does not interfere with other treatments.” See 18:10-15. The patent unfortunately does not expressly say what form of multiple sclerosis was there studied. Mention of “other treatments,” however, means that the form of MS there studied must have been the only one which in fact has “other treatments,” i.e., relapsing-remitting form MS. This patent thus fails to expressly nor implicitly teach use of andrographolide to treat any progressive form of MS.
Further, the art teaches that every other treatment for relapsing-remitting MS is ineffective for progressive forms of MS. See supra. Thus, this prior art patent failed to provide the skilled artisan a reasonable expectation of success in using the claimed compounds for any progressive form of MS.
Published PCT Application WO2013/096423 teaches the claimed compounds synergistically improve the efficacy of interferon in treating Multiple Sclerosis. See page 2 at Summary, page 8 at 7th paragraph. The art, however, teaches that interferons are not effective at all to treat progressive forms of MS. See supra. Thus, the skilled artisan would have read WO '423 to teach combining interferon with the claimed compounds to treat the relapsing-remitting form of MS, rather than a progressive form of MS. Similarly, the artisan would have read WO '423 to teach that interferon is an indispensable part of MS therapy.